Neuroinflammation is associated with essentially every neurological disorder, neurodegenerative disease, and neurodevelopmental disorder. In the brain, regulation of an inflammatory response is under the control of specific cells known as microglia, They coordinate CNS inflammation by an intricate communication network with other intrinsic cellular components to shape inflammatory responses. Brain macrophages exist in various states of activation within injured tissue and retain the capability to shift their functional phenotype within specific stages of the inflammatory response. Like other tissue macrophages, microglia provide the first line of defense against invading microbes; yet, remain unique in their ability to detect critical changes in neuronal activity and health. They are capable of actively monitoring and controlling the extracellular environment, walling off areas of the CNS from non-CNS tissue, and removing dead or damaged cells. In addition, microglia play a critical role in maintaining brain homeostasis and in facilitating synapse formation and remodeling. Alterations in the normal functions of microglia can have detrimental effects on brain development and in the ability of the brain to maintain normal functioning and plasticity. Thus, as a critical and unique central nervous system cell that is distributed across the entire nervous system, alterations in this cell and its functions may represent an a target for genetic or environmental influences that could significantly affect the structure and function of the nervous system. We have examined the process by which the microglia can be altered as a function of development, aging, and in disease states such as rodent models of human immunodeficiency virus under combined antiviral therapy, and as a function of environmental factors. We are interested in determining the regulatory factors that influence the microglia response and whether this can be altered by environmental factors. Much of our work has been associated with identifying markers of microglia activation state/polarization and understanding the functional associations with each state (phagocytosis, chemotaxis, shifts in mitochondrial bioenergetics). We are examining the ability of various environmental agents (organotins, arsenic, flame retardants, and a cluster of chemicals associated by gene profiling for neurodevelopment disruption) to modify the normal functional ability of microglia. In examining the neurotoxic potential of arsenic, we have examined the effect of acute and prolonged arsenic exposure to modify the ability of microglia to mount a normal host-response to an inflammatory event. We have identified that arsenic can shift the normal response of microglia to lipopolysaccharide for a pro-inflammatory response and to interleukin 4/ interleukin 13 to induce an anti-inflammatory response. We have also identified that under these exposure conditions the phagocytic capability of the macrophage is blunted. We have also characterized the dynamics of the bioenergetic capacity of microglia under these conditions and how they shift depending on the initiating stimulus. We have developed a reporter cell line that will allow us to examine the ability of environmental agents to serve as secondary triggers for NLRP3 inflammasome activation thus, influencing the regulatory process for inflammation and the potential to initiate a chronic inflammatory state. Using these systems as models of hindered macrophage response we are examining the impact on biological functions such as migration and phagocytic capability and developing methods to assess what impact this shift may have not only on adult response to disease or injury but also in brain development and ability to repair following injury. We have further examined the underlying mechanisms associated with the blunting of the inflammatory response or activation of the NLRP3 inflammasome as they relate to mitochondrial function. This is of importance for environmental exposures as there are a significant number of chemicals considered to affect mitochondrial function and thus may affect the inflammatory status of the organism. In addition, a link has been made between neuroinflammation, mitochondrial dysfunction, and the loss of dopaminergic neurons implicating these processes with the development and progression of Parkinson's Disease. To evaluate the impact of pro-inflammatory cytokines on the brain repair response we have developed a model system to examine the progenitor cell population from the subgranular zone of the hippocampus at different ages. Using this system as well as the in vivo model we are examining the influence of microglia and pro-inflammatory cytokines on the proliferation and differentiation of neural progenitor cells and how drug or toxicant exposure can influence this process to enhance or hinder repair. We have identified a possible pivot point distinguishing beneficial versus detrimental effects on neural progenitor cells in the hippocampus of adolescent mice in the interleukin 1 activation of the inflammasome. Thus, providing support for examining the brain immune cells as a target for neurotoxicity. For these studies we continue to use a number of methods to examine alterations in the developing nervous system following exposure to environmental agents including immunohistochemistry, con-focal imaging, flow cytometry, seahorse mitochondrial bioenergetics, molecular techniques to examine mRNA level such as qRT-PCR, microarray, RNase protection assays, neuroprogenitor cell cultures, adult derived neural stem/progenitor cells, as well as assessment of neurobehavioral functioning.